Previous studies on isolated perfused hearts and in situ dog heart preparations have demonstrated the presence of degradative products of adenosine in the cardiac effluents during periods of myocardial hypoxia. With the use of an adenosine deaminase inhibitor, adenosine could be detected in the perfusate of the isolated hypoxic heart and more recently in the coronary sinus blood of the open-chest dog during the period of reactive hyperemia following brief occlusion of the left coronary artery. Improvements in the methods for quantification of adenosine in blood have made it possible to study adenosine release under more physiological conditions and recent results indicate that adenosine plays a key role in the normal regulation of coronary blood flow. Adenosine has been found in well-oxygenated myocardium and it rapidly increases in concentration with brief (5 sec) coronary occlusions. We will now study adenosine production by the heart of the unanesthetized dog during rest and during exercise. Adenosine has also been found in increased quantities in ischemic skeletal muscle and brain as well as in venous blood from hypoxic muscle and in cerebrospinal fluid. Electrical stimuli, hypotension, decreased PO2 and PCO2 all resulted in increased adenosine levels in rat brain. Hypercapnia produced a reduction in cerebral CO2. We will now determine the effect of physiological stimuli on cerebral adenosine release and cerebral blood flow in the dog. Studies on the kidney show adenosine formation with ischemia and we will try to relate post occlusion ischemia to adenosine production. Adenosine is also produced in hypoxic lung and elicits pulmonary vasodilation. To what extent this opposes the vasoconstriction associated with hypoxia remains to be determined. The mechanism of action of adenosine as a vasodilator will be studied in vascular smooth muscle. In addition studies will be directed at intracellular localization of the enzymes involved in adenosine metabolism in various tissues, including cultured heart cells. Finally, study of the relative effects of several endogenous vasodilator substances affecting the coronary vessels will be undertaken as well as the effects of non-metabolizable analogues of adenosine on coronary blood flow. BIBLIOGRAPHIC REFERENCE: Rubio, R. and R.M. Berne. Regulation of coronary blood flow. Progress in Cardiovascular Disease. 18: 105-122, l975.